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Background Methods Results Conclusions Spinal Cord Stimulation (SCS) is an established therapy for chronic pain, employing screening trials to identify suitable candidates before implantation. However, complications arising from both technique and medical factors present challenges to this practice. This study introduces the Dural Substitute Confetti technique, which addresses technique‐related complications during SCS implantation by preventing scar‐induced lead migration or breakage and reducing operating times.We conducted a retrospective analysis on 174 patients treated with SCS trials from 2017 to 2022 at our institution. Of these, 85.1% proceeded to permanent implantation. During trial surgery, synthetic dural substitutes (DS) were used to protect leads, which remained connected to an external pulse generator (EPG) for 20–28 days (mean 21.4 days). Utilizing the DS Confetti technique, leads were easily dissected from the DS during the second surgery and connected to an internal pulse generator (IPG). We compared complications and surgical times before and after the introduction of this technique in 2017.Following the complete SCS trial, patients experienced over 50% pain relief, with an implant‐to‐trial ratio of 85.1% and a mean follow‐up of 52 months. No technique‐related complications occurred during the trial period post‐2017, while the pre‐2017 group had a 3.9% lead migration rate due to scarring, necessitating re‐implantation. The average surgery duration decreased from 54 min pre‐2017 to 32 min post‐2017. Medical‐related complications included infections (2.1%) and wound dehiscence (1.3%).The DS Confetti technique prevents scar adhesion formation during screening trials, thereby facilitating and expediting the definitive SCS implantation. Additionally, it may also reduce the risk of lead migration and iatrogenic damage, potentially lowering technique‐related complications. [ABSTRACT FROM AUTHOR]

Investigator-initiated clinical studies (IICSs), also referred to as non-commercial, academic or independent clinical studies, address important research questions that are usually neglected by industry despite their high societal value. Indeed, industry may direct their focus and resources on studies that will yield results and products that can ultimately generate revenue for the company. Conversely, IICS research questions include (a) refining or getting new indications of available treatments (drug repurposing); (b) optimisation, by comparing various health products or treatment regimens; and (c) innovation, especially for advanced therapies. Multinational IICSs increase the scientific quality of the data by exchange of research ideas, scientific techniques and tools. Participation of patients from different geographical, social and ethnic backgrounds equally adds to the value of study results and yields more generalisable evidence than a study confined to a single geographical location. Multinational IICSs are generally sponsored by non-profit/academic organisations and publicly funded. Funding has been already identified as a main challenge for the conduct IICS and especially for clinical trials (IICTs, IICS where a medical intervention is directly tested). Main barriers to the conduct of multinational IICTs with public funding include: Limitations of budget and duration of the eligibility of costs Lack of flexibility to move funds transnationally Tendering rules Complexity in the reporting of the eligible costs to funders We describe why there is a need to support multinational IICS, what should be their objectives and what are the current funding mechanisms in Europe. Strategies for funding multinational IICS should evolve to mitigate identified barriers, thus facilitating research that can provide answers to highly relevant questions in healthcare which are less likely to be answered by studies funded by the pharmaceutical and medical device industry. [ABSTRACT FROM AUTHOR]

Background: Methodological limitations affect a significant number of oncology and haematology trials, raising concerns about the applicability of their results. For example, a suboptimal control arm or limited access to best care upon progression may skew the trial results toward a benefit in the experimental arm. Beyond the fact that such limitations do not prevent drugs reaching the market, other assessment tools, such as those developed by professional societies—ESMO‐MCBS and ASCO Value Framework—do not integrate these important shortcomings. Methods: We propose creating a novel framework with the scope of assessing registration cancer clinical trials in haematology and oncology (randomized or single arm)—that is trials leading to a marketing authorization. The main steps of the methods are (1) assembling a scientific board; (2) defining the scope, goal and methods through pre‐specified, pre‐registered and protocolized methodology; (3) preregistration of the protocol; (4) conducting a scoping review of limitations and biases affecting oncology trials and assessing existing scores or methods; (5) developing a list of features to be included and assessed within the framework; (6) assessing each feature through a questionnaire sent to highly cited haematologists and oncologists involved in clinical trials; and (7) finalizing the first version of framework. Results: Not applicable. Conclusions: Our proposal emerged in response to the lack of consideration for key limitations in current trial assessments. The goal is to create a framework specifically designed to assess single trials leading to marketing authorization in the field of oncology and haematogy. [ABSTRACT FROM AUTHOR]

Aim: This is a report of the 5-year results of a two-group parallel randomized clinical trial comparing longitudinal implant stability, and clinical and radiographic peri-implant outcomes of mandibular overdentures retained by one (1-IOD group) or two (2-IOD group) implants. Methods: All participants received 4.1 mm diameter tissue-level implants (Straumann® Standard Plus – SLActive®, Institut Straumann AG), installed in the mandible midline (1-IOD; n = 23) or the lateral incisor-canine area bilaterally (2-IOD; n = 24), and loaded after 3 weeks. Implant Stability Quotient (ISQ) was measured using a resonance frequency device (Osstell® Mentor, Integration Diagnostics) at implant placement, after three weeks (loading), and at the 6-month, 1-, 3-, and 5-year follow-ups. Marginal bone loss and clinical implant outcomes (plaque, calculus, suppuration and bleeding) were assessed periodically up to 5 years after loading. Results: Only minor changes in marginal bone level were observed after 5 years (mean = 0.37; SD = 0.44 mm), and satisfactory and stable peri-implant parameters were observed throughout the 5-year follow-up. No significant differences between groups were found. Overall, the mean primary implant stability was considered high (> 70) for the two groups (1-IOD = 78.1 ± 4.5; 2-IOD = 78.0 ± 5.8). No noticeable changes were observed between implant insertion and loading. A marked increase was observed from insertion to the 6-month follow-up – the mean difference for the 1-IOD group was + 5.5 ± 5.5 (Effect size = 1.00), while for the 2-IOD group, the mean difference was + 6.0 ± 5.6 (Effect size = 1.08). No relevant changes were observed throughout the follow-up periods up to 5 years. Linear mixed-effect model regression showed no influence of the bone-related variables (p > 0.05) and the number of implants (p = 0.087), and a significant effect of the time variable (p < 0.001). Conclusion: Satisfactory peri-implant outcomes and stable secondary stability suggest good clinical performance and successful long-term osseointegration of the implants for single and two-implant mandibular overdentures. Using a single implant to retain a mandibular overdenture does not seem to result in detrimental implant loading over the five years of overdenture use. Clinical relevance: This study corroborates the use of a single implant to retain a mandibular denture. [ABSTRACT FROM AUTHOR]

The trials in Shakespeare's plays are strange. There are no lawyers or professional judges, there may be no witnesses, and the adjudicator often imposes unusual sanctions such as banishment. Most strikingly, almost all the trials are fakes, manipulated by a character toward a predestined result. Two obvious explanations—that trials in Shakespeare's day were like that, and that trials in the contemporary drama were like that—turn out to be largely incorrect. It is more persuasive to trace the strange features of Shakespeare's trials to the various dramatic functions they fulfill, yet even this approach does not explain everything. [ABSTRACT FROM AUTHOR]

Introduction: Screening trials and meta-analyses emphasize the ratio of cancer death rates in screening and control arms. However, this measure is diluted by the inclusion of deaths from cancers that only became detectable after the end of active screening. Methods: We review traditional analysis of cancer screening trials and show that ratio estimates are inevitably biased to the null, because follow-up (FU) must continue beyond the end of the screening period and thus includes cases only becoming detectable after screening ends. But because such cases are expected to occur in equal numbers in the two arms, calculation of the difference between the number of cancer deaths in the screening and control arms avoids this dilutional bias. This difference can be set against the number of invitations to screening; we illustrate by reanalyzing data from all trials of tomography screening of lung cancer (LC) using this measure. Results: In nine trials of LC screening from 2000 to 2013, a total of 94,441 high-risk patients were invited to be in screening or control groups, with high participation rates (average 95%). In the older trials comparing computed tomography to chest X-ray, 88,285 invitations averted 83 deaths (1068 per death averted (DA)). In the six more recent trials with no screening in the control group, 69,976 invitations averted 121 deaths (577 invitations per DA). Discussion: Screens per DA is an undiluted measure of screening's effect and it is unperturbed by the arbitrary duration of FU. This estimate can be useful for program planning and informed consent. [ABSTRACT FROM AUTHOR]

The number needed to treat (NNT) is the inverse of the absolute risk difference, which is used as a secondary outcome to clinical trials as a measure relevant to a positive trial, supplementing statistical significance. The NNT requires dichotomous outcomes and is influenced by the baseline disease or symptom severity, the particular population, the type and intensity of the interventional, the duration of treatment, the time period to assessment of response, and the comparator response. Confidence intervals should always accompany NNT for the precision of its estimate. In this review, three meta-analyses are reviewed, which included the NNT in the analysis of response. [ABSTRACT FROM AUTHOR]

Angiogenesis is critical for tumor growth and metastasis. Bevacizumab is an antiangiogenic drug used to treat various adult and childhood solid tumors. Its potential efficacy in Wilms tumor (WT) with poor prognosis is not established. The response to bevacizumab-containing regimens in relapsed or refractory WT was reviewed in available literature. Searches were conducted using PubMed, Scopus, and ClinicalTrials.gov databases. Eight papers were identified, published between 2007 and 2020, including six treatment regimens, predominantly vincristine, irinotecan, and bevacizumab (VIB) ± temozolomide (VITB). Among 16 evaluable patients, there were two complete responses, seven partial responses, five patients achieved stable disease (SD), and two patients had progressive disease. Objective responses (OR) were observed in 56% of all cases. OR or SD was observed in 89% (8/9) patients who received VIB/VITB. Bevacizumab was generally well tolerated. Related toxicities included hypertension, proteinuria, and delayed wound healing. This review suggests potential effectiveness and good tolerability of bevacizumab in the setting of relapsed/refractory WT when used in combination with other drugs. Such combination therapies may serve as a bridging treatment option to other interventions and more personalized treatment options in the future; however, focused trials are needed to obtain additional evidence. [ABSTRACT FROM AUTHOR]

Human Immunodeficiency Virus (HIV) remains a significant global health challenge with approximately 38 million people currently having the virus worldwide. Despite advances in treatment development, the virus persists in the human population and still leads to new infections. The virus has a powerful ability to mutate and hide from the human immune system in reservoirs of the body. Current standard treatment with antiretroviral therapy effectively controls viral replication but requires lifelong adherence and does not eradicate the virus. This review explores the potential of Advanced Therapy Medicinal Products as novel therapeutic approaches to HIV, including cell therapy, immunisation strategies and gene therapy. Cell therapy, particularly chimeric antigen receptor T cell therapy, shows promise in preclinical studies for targeting and eliminating HIV-infected cells. Immunisation therapies, such as broadly neutralising antibodies are being investigated to control viral replication and reduce reservoirs. Despite setbacks in recent trials, vaccines remain a promising avenue for HIV therapy development. Gene therapy using technologies like CRISPR/Cas9 aims to modify cells to resist HIV infection or eliminate infected cells. Challenges such as off-target effects, delivery efficiency and ethical considerations persist in gene therapy for HIV. Future directions require further research to assess the safety and efficacy of emerging therapies in clinical trials. Combined approaches may be necessary to achieve complete elimination of the HIV reservoir. Overall, advanced therapies offer new hope for advancing HIV treatment and moving closer to a cure. [ABSTRACT FROM AUTHOR]

Abstract Investigator-initiated clinical studies (IICSs), also referred to as non-commercial, academic or independent clinical studies, address important research questions that are usually neglected by industry despite their high societal value. Indeed, industry may direct their focus and resources on studies that will yield results and products that can ultimately generate revenue for the company. Conversely, IICS research questions include (a) refining or getting new indications of available treatments (drug repurposing); (b) optimisation, by comparing various health products or treatment regimens; and (c) innovation, especially for advanced therapies. Multinational IICSs increase the scientific quality of the data by exchange of research ideas, scientific techniques and tools. Participation of patients from different geographical, social and ethnic backgrounds equally adds to the value of study results and yields more generalisable evidence than a study confined to a single geographical location. Multinational IICSs are generally sponsored by non-profit/academic organisations and publicly funded. Funding has been already identified as a main challenge for the conduct IICS and especially for clinical trials (IICTs, IICS where a medical intervention is directly tested). Main barriers to the conduct of multinational IICTs with public funding include: Limitations of budget and duration of the eligibility of costs Lack of flexibility to move funds transnationally Tendering rules Complexity in the reporting of the eligible costs to funders We describe why there is a need to support multinational IICS, what should be their objectives and what are the current funding mechanisms in Europe. Strategies for funding multinational IICS should evolve to mitigate identified barriers, thus facilitating research that can provide answers to highly relevant questions in healthcare which are less likely to be answered by studies funded by the pharmaceutical and medical device industry.

Abstract Background In 2015, the results of the ‘Small bites versus large bites for closure of abdominal midline incisions (STITCH) Trial’ were published in The Lancet. This demonstrated the superiority of small bite laparotomy closure over mass closure for the reduction of incisional hernias; despite this most surgeons have not changed their practice. Previous research has shown the time taken for the implementation of evidenced based practise within medicine takes an average of 17 years. This study aims to understand the reasons why surgeons have and have not changed their practice with regards to closure of midline laparotomy. Methods Semi-structured interviews were completed with surgical consultants and registrars at a single institution in South West England. The interview topic guide was informed by a review of the published literature, which identified barriers to adopting evidence into surgical practice. Interview transcripts underwent thematic analysis with themes identified following discussions within the research team, exploring views on published data and clinical practise. Results Nine interviews with general surgical and urological consultants as well as registrars in training were performed. Three themes were identified; ‘Trusting the Evidence & Critical Appraisal’, ‘Surgical Attitude to Risk’ and ‘Adopting Evidence in Practise’, that reflected barriers to the introduction of evidenced based practise to clinical work. Conclusion Identification of the themes highlights possible areas for intervention to decrease the adoption time for evidence, for example from randomised controlled trials. The continued updating of clinical practise allows clinicians to provide best evidenced based care for patients and improve their outcomes.

Abstract Background Participants in research trials often disclose severe depression symptoms, including thoughts of self-harm and suicidal ideation, in validated self-administered questionnaires such as the Patient Health Questionnaire (PHQ-9). However, there is no standard protocol for responding to such disclosure, and the opportunity to support people at risk is potentially missed. We developed and evaluated a risk assessment protocol for the IBD-BOOST randomised controlled trial (ISRCTN71618461 09/09/2019). Methods Participants completed the PHQ-9 at baseline and 6-month and 12-month follow-ups. The trial database automatically alerted the research team to risk assess participants. Trial researchers, trained in the protocol, contacted participants by telephone, completed the risk assessment, and signposted participants to appropriate professional services. Results Seven hundred eighty participants were randomised in the trial; 41 required risk assessment. One participant declined assessment, so 40 risk assessments were completed. Twenty-four participants were assessed as low-risk and 16 participants as medium-risk, with 12 declaring previous suicide attempts. None were rated as high-risk. Trial participants expressed appreciation for being contacted, and all except two wished to receive information about professional support services. Trial risk assessors reported positive experiences of conducting the risk assessment with suggestions for improvement, which resulted in minor modifications to the protocol. Discussion Our evaluation demonstrated that it was viable for a research trial team to successfully conduct a risk-assessment protocol for trial participants reporting thoughts of self-harm, with training and support from senior colleagues. Resources are required for training and delivery, but it is not unduly onerous. Trial participants appeared to find completing the assessment acceptable.

Abstract Regulatory agencies require evidence that endpoints correlate with clinical benefit before they can be used to approve drugs. Biomarkers are often considered surrogate endpoints. In cancer cachexia trials, the measurement of biomarkers features frequently. The aim of this systematic review was to assess the frequency and diversity of biomarker endpoints in cancer cachexia trials. A comprehensive electronic literature search of MEDLINE, Embase and Cochrane (1990–2023) was completed. Eligible trials met the following criteria: adults (≥18 years), prospective design, more than 40 participants, use of a cachexia intervention for more than 14 days and use of a biomarker(s) as an endpoint. Biomarkers were defined as any objective measure that was assayed from a body fluid, including scoring systems based on these assays. Routine haematology and biochemistry to monitor intervention toxicity were not considered. Data extraction was performed using Covidence, and reporting followed PRISMA guidance (PROSPERO: CRD42022276710). A total of 5975 studies were assessed, of which 52 trials (total participants = 6522) included biomarkers as endpoints. Most studies (n = 29, 55.7%) included a variety of cancer types. Pharmacological interventions (n = 27, 51.9%) were most evaluated, followed by nutritional interventions (n = 20, 38.4%). Ninety‐nine different biomarkers were used across the trials, and of these, 96 were assayed from blood. Albumin (n = 29, 55.8%) was assessed most often, followed by C‐reactive protein (n = 22, 42.3%), interleukin‐6 (n = 16, 30.8%) and tumour necrosis factor‐α (n = 14, 26.9%), the latter being the only biomarker that was used to guide sample size calculations. Biomarkers were explicitly listed as a primary outcome in six trials. In total, 12 biomarkers (12.1% of 99) were used in six trials or more. Insulin‐like growth factor binding protein 3 (IGFBP‐3) and insulin‐like growth factor 1 (IGF‐1) levels both increased significantly in all three trials in which they were both used. This corresponded with a primary outcome, lean body mass, and was related to the pharmacological mechanism. Biomarkers were predominately used as exploratory rather than primary endpoints. The most commonly used biomarker, albumin, was limited by its lack of responsiveness to nutritional intervention. For a biomarker to be responsive to change, it must be related to the mechanism of action of the intervention and/or the underlying cachexia process that is modified by the intervention, as seen with IGFBP‐3, IGF‐1 and anamorelin. To reach regulatory approval as an endpoint, the relationship between the biomarker and clinical benefit must be clarified.

Summary The optimal therapeutic approach for relapsed/refractory (R/R) Waldenström's Macroglobulinaemia (WM) has not been clearly defined, especially after treatment with chemoimmunotherapy (CIT) and covalent Bruton's tyrosine kinase inhibitors (cBTKi). The PembroWM trial is a multi‐centre, phase II, single‐arm study assessing the safety, tolerability and efficacy of rituximab with pembrolizumab in R/R WM patients who had received at least one prior line of treatment, with all having relapsed post‐CIT and most also exposed to cBTKi. A total of 17 patients were enrolled, with a median age of 70, and median of three prior lines of therapy with 15 either refractory or intolerant of a cBTKi. A significant proportion was identified as genomically high risk with BTKC481, CXCR4 and MYD88 L265P wild‐type aberrations. Twenty‐four‐week overall response rate was 50% (60% CI 39.3%–60.7%), and median duration of response was 11.6 months (IQR: 6.3–17). The median progression‐free survival was 13.6 months (95% CI 3–19.8), and the median overall survival (OS) was not reached. Treatment was well tolerated, with minimal numbers of immune‐mediated AEs typically seen with checkpoint inhibitors. PembroWM is the first study to evaluate the feasibility of PD‐1 axis modulation in WM and has shown that in combination with Rituximab the combination is safe and deliverable. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide OBJECTIVES Clinical trials that are terminated prematurely may generate incomplete and potentially biased data and the reasons for premature trials termination are poorly understood. Our objective was to describe the incidence of premature trial termination and identify factors associated with it. METHODS We performed a systematic search on ClinicalTrials.gov to identify all cardiac surgery trials from 1991 to 2023. Trials that were terminated prematurely were identified. Factors independently associated with premature termination were identified using multivariable logistic regression analysis. RESULTS A total of 746 clinical trials were included; of them 577 were completed and 169 (22.6%) were terminated prematurely. Most of the trials originated from North America [294 (39.4%)], Europe [264 (35.4%)] or Asia [141 (18.9%)]. Fourteen of the trials terminated prematurely (8.3%) were phase 1, 75 (44.4%) phase 2, 49 (29.0%) phase 3 and 31 (18.3%) phase 4. Fifty (29.6%) trials were terminated because of slow recruitment, 20 (11.8%) because of sponsor decision and 12 (7.1%) because of lack of funding. Left ventricular assist device trials [odds ratio (OR) 3.65, 95% confidence interval (CI) (1.65–8.00) P  = 0.001], valve surgery trials [OR 4.30, 95% CI (2.33–8.00) P  < 0.001], aortic surgery trials [OR 2.86 95% CI (1.22–6.43) P  = 0.012], phase 2 [OR 3.02, 95% CI (1.31–7.93) P  = 0.015] and phase 4 trials [OR 3.62, 95% CI (1.43–10.23) P  = 0.010] were at higher risk of premature termination while trials performed in Asia [OR 0.18, 95% CI (0.07–0.39) P  ≤ 0.001] and Europe [OR 0.49, 95% CI (0.30–0.80) P  = 0.004] were less likely to be terminated prematurely. CONCLUSIONS Slow recruitment is the most common reason for premature termination of cardiac surgery trials. Trials on left ventricular assist device, valve surgery, aortic surgery, phase 2 trials and phase 4 trials are more likely to be terminated, while trials conducted in Asia and Europe are less likely to be terminated prematurely. [ABSTRACT FROM AUTHOR]

Background: In 2015, the results of the 'Small bites versus large bites for closure of abdominal midline incisions (STITCH) Trial' were published in The Lancet. This demonstrated the superiority of small bite laparotomy closure over mass closure for the reduction of incisional hernias; despite this most surgeons have not changed their practice. Previous research has shown the time taken for the implementation of evidenced based practise within medicine takes an average of 17 years. This study aims to understand the reasons why surgeons have and have not changed their practice with regards to closure of midline laparotomy. Methods: Semi-structured interviews were completed with surgical consultants and registrars at a single institution in South West England. The interview topic guide was informed by a review of the published literature, which identified barriers to adopting evidence into surgical practice. Interview transcripts underwent thematic analysis with themes identified following discussions within the research team, exploring views on published data and clinical practise. Results: Nine interviews with general surgical and urological consultants as well as registrars in training were performed. Three themes were identified; 'Trusting the Evidence & Critical Appraisal', 'Surgical Attitude to Risk' and 'Adopting Evidence in Practise', that reflected barriers to the introduction of evidenced based practise to clinical work. Conclusion: Identification of the themes highlights possible areas for intervention to decrease the adoption time for evidence, for example from randomised controlled trials. The continued updating of clinical practise allows clinicians to provide best evidenced based care for patients and improve their outcomes. [ABSTRACT FROM AUTHOR]

Aging is a complex process and a significant risk factor for chronic diseases. Menopause, a component of aging in women, is associated with several important cardiometabolic conditions including metabolic syndrome, osteoporosis, and cardiovascular diseases. Menopausal women could benefit from preventative strategies that may decrease morbidity and mortality and improve their quality of life. Vitamins D and K are essential nutrients required for bone health, immune function, and reducing cardiovascular risks, yet their synergistic effect is less understood in aging women. This is the first comprehensive review to summarize the evidence found in randomized clinical trials of the beneficial effects of vitamin D and K co-treatment in postmenopausal women. In our literature search across key electronic databases such as Cochrane, PubMed, and Ovid, we identified 31 pertinent studies. Overall, significant findings indicate that the combined intake of vitamins D and K may positively affect cardiovascular and bone health in postmenopausal women, emphasizing the importance of maintaining a healthy diet rich in vegetables and fermented dairy products. Given the challenges in obtaining all necessary nutrients solely through the diet, vitamin D and K supplements are recommended for postmenopausal women to promote healthy aging and well-being. [ABSTRACT FROM AUTHOR]

Background: Participants in research trials often disclose severe depression symptoms, including thoughts of self-harm and suicidal ideation, in validated self-administered questionnaires such as the Patient Health Questionnaire (PHQ-9). However, there is no standard protocol for responding to such disclosure, and the opportunity to support people at risk is potentially missed. We developed and evaluated a risk assessment protocol for the IBD-BOOST randomised controlled trial (ISRCTN71618461 09/09/2019). Methods: Participants completed the PHQ-9 at baseline and 6-month and 12-month follow-ups. The trial database automatically alerted the research team to risk assess participants. Trial researchers, trained in the protocol, contacted participants by telephone, completed the risk assessment, and signposted participants to appropriate professional services. Results: Seven hundred eighty participants were randomised in the trial; 41 required risk assessment. One participant declined assessment, so 40 risk assessments were completed. Twenty-four participants were assessed as low-risk and 16 participants as medium-risk, with 12 declaring previous suicide attempts. None were rated as high-risk. Trial participants expressed appreciation for being contacted, and all except two wished to receive information about professional support services. Trial risk assessors reported positive experiences of conducting the risk assessment with suggestions for improvement, which resulted in minor modifications to the protocol. Discussion: Our evaluation demonstrated that it was viable for a research trial team to successfully conduct a risk-assessment protocol for trial participants reporting thoughts of self-harm, with training and support from senior colleagues. Resources are required for training and delivery, but it is not unduly onerous. Trial participants appeared to find completing the assessment acceptable. [ABSTRACT FROM AUTHOR]

There is often stigma attached to being the victim of state violence, as being targeted by state violence is often seen as proof that a person is guilty. This article discusses whether trials as part of transitional justice can challenge such stigma. Trials can provide a legal truth, through identifying what has happened, who the perpetrators are, and who the victim is. Trials and court hearings are an expression of what societies accept, and when a perpetrator is sentenced it is an expression of solidarity with the victim. The article compares how persons targeted by state violence by former regimes in Argentina and Peru describe and perceive of such stigma, how stigma has changed over time and with contemporary trials. There are important differences between the countries regarding the violent history, the groups targeted by state violence, and the ongoing trials, also regarding the outcome of the trials. [ABSTRACT FROM AUTHOR]

To evaluate the reporting of race/ethnicity data in randomized controlled trials (RCTs) of attention-deficit/hyperactivity disorder (ADHD) medications. Secondary objectives were to estimate temporal trends in the reporting, and to compare the pooled prevalence of racial/ethnic groups in RCTs conducted in the US to national estimates. We drew on, adapted, and updated the search of a network meta-analysis by Cortese et al. (2018) up to March 2022. We calculated the percentage of RCTs reporting data on race/ethnicity of participants in the published article or in related unpublished material. Temporal trends were estimated with logistic regression. The pooled prevalence of each racial/ethnic group across US RCTs was calculated using random-effects model meta-analyses. We retained 310 RCTs (including 44,447 participants), of which 231 were conducted in children/adolescents, 78 in adults, and 1 in both. Data on race/ethnicity were reported in 59.3% of the RCTs (75% of which were conducted in children/adolescents and 25% in adults) in the published article, and in unpublished material in an additional 8.7% of the RCTs. Reporting improved over time. In the US RCTs, Asian and White individuals were under- and overrepresented, respectively, compared to national estimates in the most recent time period considered. More than 30% of the RCTs of ADHD medications retained in this review did not include data on race/ethnicity in their published or unpublished reports, and more than 40% in their published articles, even though reporting improved over time. Results should inform investigators, authors, editors, regulators, and study participants in relation to efforts to tackle inequalities in ADHD research. A systematic review of 310 randomized controlled trials for attention-deficit/hyperactivity disorder (ADHD) medications found that race/ethnicity were reported in only 30% of trials. Compared to national estimates, Asian individuals were underrepresented and non-Hispanic Whites individuals were overrepresented, drawing attention to the inequities in participation in ADHD research. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. We actively worked to promote sex and gender balance in our author group. While citing references scientifically relevant for this work, we also actively worked to promote sex and gender balance in our reference list. While citing references scientifically relevant for this work, we also actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our reference list. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work. Reporting and representation of race/ethnicity in double blind randomised controlled trials of medications for ADHD; https://osf.io/ ; hfgz8. [ABSTRACT FROM AUTHOR]

Population‐based organised repeated screening for prostate cancer has been found to reduce disease‐specific mortality, but with substantial overdiagnosis leading to overtreatment. Although only very few countries have implemented a screening programme on a national level, individual prostate‐specific antigen (PSA) testing is common. This opportunistic testing may have little favourable impact, while stressing the side‐effects. The classic early detection protocols as were state‐of‐the‐art in the 1990s applied a PSA and digital rectal examination threshold for sextant systematic prostate biopsy, with a fixed interval for re‐testing, and limited indication for expectant management. In the three decades since these trials were started, different important improvements have become available in the cascade of screening, indication for biopsy, and treatment. The main developed aspects include: better identification of individuals at risk (using early/baseline PSA, family history, and/or genetic profile), individualised re‐testing interval, optimised and individualised starting and stopping age, with gradual invitation at a fixed age rather than invitation of a wider range of age groups, risk stratification for biopsy (using PSA density, risk calculator, magnetic resonance imaging, serum and urine biomarkers, or combinations/sequences), targeted biopsy, transperineal biopsy approach, active surveillance for low‐risk prostate cancer, and improved staging of disease. All these developments are suggested to decrease the side‐effects of screening, while at least maintaining the advantages, but Level 1 evidence is lacking. The knowledge gained and new developments on early detection are being tested in different prospective screening trials throughout Europe. In addition, the European Union‐funded PRostate cancer Awareness and Initiative for Screening in the European Union (PRAISE‐U) project will compare and evaluate different screening pilots throughout Europe. Implementation and sustainability will also be addressed. Modern screening approaches may reduce the burden of the second most frequent cause of cancer‐related death in European males, while minimising side‐effects. Also, less efficacious opportunistic early detection may be indirectly reduced. [ABSTRACT FROM AUTHOR]

Flexible sigmoidoscopy (FS), which is less invasive, resource intensive and costly than colonoscopy, is among the recommended screening options for colorectal cancer (CRC). Four large randomized trials consistently reported statistically significant, albeit modest effects of screening by FS on CRC incidence. However, their effect estimates included cancers that were already prevalent at recruitment and could not have been prevented by screening. We performed a re-analysis and meta-analysis of two of the trials (including the largest one) to estimate reduction of truly incident cases by a single FS offered between 55 and 64 years of age among the "at risk study population" without prevalent CRC at recruitment. In meta-analyses of data reported after more than 15 years of follow-up, relative risk (95% CI) in intention-to-screen and per-protocol analyses were 0.71 (0.66–0.76) and 0.59 (0.55–0.65) for any CRC, and 0.52 (0.47–0.57) and 0.34 (0.30–0.39) for distal CRC, respectively. These results indicate much stronger effects than those suggested by the original reports and imply that a single screening FS can prevent approximately two out of three distal incident CRC cases within 15 + years of follow-up. [ABSTRACT FROM AUTHOR]

Trial excessive duration is a common problem in Juridical systems worldwide, even if some countries seem to be more affected by it than others. The European Council has provided metrics and statistics to identify this problem and has pointed out solutions, such as the simplification of norms and the digitization of Juridical procedures. The Italian Telematic Civil Process (TCP) is an example of this digitization effort that has surely positively influenced the duration of Trials, their traceability and general complexity. However, there are still many possible actions that can be taken to simplify the work of Judges and Chancellors, and to support their daily operations in dealing with several Trials at once, and with the consistent number of documents that are involved in them. This paper presents a toolchain and a related methodology for the management of documentation attached to Trials, based on semantic technologies and Natural Language Processing techniques, which will help Judges in faster assessing the situation of each Trial they follow, and will also provide the means to identify potential correlations among different Juridical procedures. The methodology is tested against a case study, i.e. the compensation requests related to road accidents, which has been provided and described by Domain Experts from the Italian Ministry of Justice. [ABSTRACT FROM AUTHOR]

Acute respiratory distress syndrome (ARDS) is characterized by acute inflammatory injury to the lungs, alterations in vascular permeability, loss of aerated tissue, bilateral infiltrates, and refractory hypoxemia. ARDS is considered a heterogeneous syndrome, which complicates the search for effective therapies. The goal of this review is to provide an update on the pharmacological management of ARDS. The difficulties in finding effective pharmacological therapies are mainly due to the challenges in designing clinical trials for this unique, varied population of critically ill patients. Recently, some trials have been retrospectively analyzed by dividing patients into hyper-inflammatory and hypo-inflammatory sub-phenotypes. This approach has led to significant outcome improvements with some pharmacological treatments that previously failed to demonstrate efficacy, which suggests that a more precise selection of ARDS patients for clinical trials could be the key to identifying effective pharmacotherapies. This review is provided after searching the main studies on this topics on the PubMed and clinicaltrials.gov databases. The future of ARDS therapy lies in precision medicine, innovative approaches to drug delivery, immunomodulation, cell-based therapies, and robust clinical trial designs. These should lead to more effective and personalized treatments for patients with ARDS. [ABSTRACT FROM AUTHOR]

The need for a stronger evidence-base in paramedicine has precipitated a rapid development of prehospital research agendas. Paramedics are increasingly involved in research, leading to changes in their role. Yet, the integration of research responsibilities has proven to be challenging, resulting in varying attitudes and levels of engagement. This systematic review aimed to explore paramedics' views and experiences of research as researchers during training and within practice. A systematic search was performed across six databases. Qualitative empirical peer-reviewed articles that discussed paramedic perspectives on engaging with research activity were included. Of 10,594 articles identified initially, 11 were included in the final synthesis after quality appraisal. Data were extracted and subjected to narrative synthesis. The following four themes were identified: motivation to engage, moral dilemmas, structural issues within the profession, and reflections on trial involvement. Attitudes toward research, understanding of related concepts, and the drive for patient benefit were interwoven core issues. Research was highly valued when links to patient benefit were obvious, however, this review highlights some cultural resistance to research, particularly regarding informed consent and changes to standard practice. Paramedic research methods training should provide structured opportunities to explore concerns and emphasize the role of research in developing a high-quality evidence base to underpin safe practice. Currently, there is inadequate organizational support for paramedics to engage effectively in research activity, with minimal allocations of time, training, and remuneration. Without properly integrating research activity into the paramedic role, their capacity to engage with research activity is limited. [ABSTRACT FROM AUTHOR]

Esophagectomy is a complex and complication laden procedure. Despite centralization, variations in perioparative strategies reflect a paucity of evidence regarding optimal routines. The use of nasogastric (NG) tubes post esophagectomy is typically associated with significant discomfort for the patients. We hypothesize that immediate postoperative removal of the NG tube is non-inferior to current routines. All Nordic Upper Gastrointestinal Cancer centers were invited to participate in this open-label pragmatic randomized controlled trial (RCT). Inclusion criteria include resection for locally advanced esophageal cancer with gastric tube reconstruction. A pretrial survey was undertaken and was the foundation for a consensus process resulting in the Kinetic trial, an RCT allocating patients to either no use of a NG tube (intervention) or 5 days of postoperative NG tube use (control) with anastomotic leakage as primary endpoint. Secondary endpoints include pulmonary complications, overall complications, length of stay, health related quality of life. A sample size of 450 patients is planned (Kinetic trial: https://www.isrctn.com/ISRCTN39935085). Thirteen Nordic centers with a combined catchment area of 17 million inhabitants have entered the trial and ethical approval was granted in Sweden, Norway, Finland, and Denmark. All centers routinely use NG tube and all but one center use total or hybrid minimally invasive-surgical approach. Inclusion began in January 2022 and the first annual safety board assessment has deemed the trial safe and recommended continuation. We have launched the first adequately powered multi-center pragmatic controlled randomized clinical trial regarding NG tube use after esophagectomy with gastric conduit reconstruction. [ABSTRACT FROM AUTHOR]

While morphine is the recommended first-line treatment for pain management in patients with acute coronary syndrome, recent studies have raised concerns about its association with adverse outcomes. Morphine has been found to cause delayed antiplatelet effects, decreased ticagrelor absorption, increased platelet reactivity, and compromised efficacy of dual antiplatelet therapy (DAPT). Alternative analgesics, such as lidocaine, fentanyl, and acetaminophen, have begun to emerge as viable alternatives, each with unique mechanisms and potential benefits. Lidocaine is demonstrated to have superior effects in reducing microvascular obstruction and fewer adverse events compared to fentanyl, despite being less effective in pain reduction. Fentanyl, which shows rapid onset and powerful analgesic properties, may interfere with ticagrelor absorption, potentially affecting platelet inhibition. Acetaminophen, a centrally acting analgesic, emerges as a safer alternative with comparable pain relief efficacy and minimal side effects. The results of multiple clinical trials emphasize the significance of customizing pain management approaches to match individual patient profiles and achieving the optimal balance between pain relief and potential adverse outcomes. [ABSTRACT FROM AUTHOR]

Atopic Dermatitis is the most common eczematous inflammatory skin condition, presenting with lesions that typically appear as poorly demarcated erythematous and scaly papules and plaques. The lesions most commonly occur on flexural surfaces of the knees, elbows, and wrists and are associated with moderate to severe itching. This article focuses on the clinical presentation of atopic dermatitis and treatment options. Other related topics include epidemiology, pathogenesis, risk factors, triggers, and differential diagnoses. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Tikrit University for Humanities is the property of Republic of Iraq Ministry of Higher Education & Scientific Research (MOHESR) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

This paper presents the design of an integrated potato-planting machine capable of full-film covering, creating micro-ditches on ridges, and covering seed rows with soil. The machine addresses the challenges of traditional methods, allowing for mechanized planting with complete film coverage and individual seed row soil covering. The key components of the prototype were analyzed and designed. This includes the seeding system, the pointed wing-shaped trencher for creating micro-ditches, and the straddling film-mulching device. Additionally, the operating mechanism of these core components was analyzed. Field trials demonstrated an 85% success rate for seed depth placement under the film. The machine also achieved a 90% qualified index for seed potato spacing, with a 6% repetitive seeding rate and a 3% missed seeding rate. Furthermore, the qualified rate for covered soil width on seed rows was 94%, and the qualified rate for covered soil thickness was 93%. The adjacent row spacing achieved an 88% success rate. The degree of mechanical damage to the exposed surface of the mulch film was minimal, at only 30.2 mm2/m2. These results meet all the national and industry standards. The successful field trials confirm the effectiveness of the machine in performing integrated fertilization, sowing, ridging, full-film covering, and seed row soil covering. Compared to traditional methods, this machine significantly reduces labor intensity for farmers and enhances the economic value of potato planting. [ABSTRACT FROM AUTHOR]

In the Federal Republic of Germany, the 1964 law banning the recording and broadcasting of court hearings was preceded by more than a decade of debate, initially centred on the presence of microphones in courtrooms before the rise of television in the late 1950s. This paper analyses those discussions based on court archives documents, which shed light on both the discourses of the stakeholders and the practices adopted in the courts. The debates should also be seen in the context of new challenges facing the judicial institution, including the democracy-building process, while many of the judicial stakeholders remained the same as before 1945. The analysis shows that radio succeeded in carving out a – fragile – place for itself in West German courts. A critical discourse denouncing the presence of microphones as illegitimate and dangerous coexisted with a more open discourse, albeit in a minority. However, the position of the judiciary gradually hardened and, from 1959 onwards, against the backdrop of increasing tension between the judiciary and the media, there was a massive demand for a general ban on recordings.

The singularity of the recordings made in the Justice Ministry’s audio-visual archives gives them a special place in the French Heritage Code compared with other archives. Its history and legal status explain its specific features. Thanks to the Law of the 11th of July 1985 as advocated by then Minister of Justice, Robert Badinter, cameras have been allowed into courtrooms, to constitute the memory of the Judiciary through historical video or sound archives, in their entirety, without cuts, additions or editing.This new law broke the ban on filming or photographing trials, which dated back to 1954. Since then, 28 trials have been recorded: crimes committed during the Second World War, crimes against humanity, crimes of genocide against the Tutsi in Rwanda, crimes of terrorist attacks. The historical subjects characterise their recording. Accessing and consulting these archives is a social, educational and remembrance issue.

During the trials of the terrorist attacks, between 2021 and 2024, two archivists from the National Archives of France went into the courtrooms to document the judicial action live, synchronising themselves with the complete recordings from the Justice Ministry’s audio-visual archives recorded during the 1,334 hours of filming. From this privileged placz, observation of the video recordings raises questions about the place that sound occupies in the creation of this archive. Faced with the material organisation used to reproduce it - fixed microphones, web radio – there is a more sensitive experience of the oral nature of the judicial debate. This very contemporary point of view invites us to go back in time to the first moving image recordings of trials, which were initially silent until their recording was banned in 1954. The return of the camera, wanted by Robert Badinter in 1985, is an archiving tool that also fixes the sound, restoring the materiality of filmed trials and inscribing them in our memory.

Abstract Background Surgical trials are recognised as inherently challenging. Pilot and feasibility studies (PAFS) are increasingly acknowledged as a key method to optimise the design and conduct of randomised trials but remain limited in surgery. We used a mixed methods approach to develop recommendations for how surgical PAFS could be optimised. Methods The findings from a quantitative analysis of funded surgical PAFS over a 10-year period and in-depth qualitative interviews with surgeons, methodologists and funders were triangulated and synthesised with available methodological guidance on PAFS. Results The synthesis informed the development of an explanatory model describing root causes and compounding challenges that contribute to how and why surgical PAFS is not currently optimised. The four root causes identified include issues relating to (i) understanding the full scope of PAFS; (ii) design and conduct of PAFS; (iii) reporting of PAFS; and (iv) lack of appreciation of the value of PAFS by all stakeholder groups. Compounding challenges relate to both cultural issues and access to and interpretation of available methodological PAFS guidance. The study findings and explanatory model were used to inform the development of a practical guidance tool for surgeons and study teams to improve research practice. Conclusions Optimisation of PAFS in surgery requires a cultural shift in research practice amongst funders, academic institutions, regulatory bodies and journal editors, as well as amongst surgeons. Our ‘Top Tips’ guidance tool offers an accessible framework for surgeons designing PAFS. Adoption and utilisation of these recommendations will optimise surgical PAFS, facilitating successful and efficient future surgical trials.

Background Aims Materials and Methods Results Discussion Conclusion Low‐intensity interventions targeting a range of mental health issues offer a scalable approach for young trauma survivors in low‐middle income countries.Here, we present results from a proof‐of‐concept, randomized, waitlist‐controlled trial evaluating MemFlex, an autobiographical memory‐based intervention, for trauma‐exposed Afghan youth residing in Iran. MemFlex seeks to reduce the negative and overgeneral memory biases which maintain and predict poor mental health.Young people aged 12–18 years (N = 40) with parents who had experienced forced migration from Afghanistan were recruited from high schools in Karaj City in Iran. All had experienced a traumatic event in the last year. Participants were randomized to receive four weeks of a group‐based delivery of MemFlex or Waitlist. Our primary cognitive outcome was autobiographical memory flexibility, that is, the ability to deliberately retrieve any memory type on demand. Primary clinical outcome was emotional distress, measured on the Farsi version of the Hopkins Symptom Checklist.Results indicated that MemFlex participants demonstrated large effect sizes for pre‐to‐post improvement in memory flexibility (d = 2.04) and emotional distress (d = 1.23). These improvements were significantly larger than Waitlist (ds < .49), and were maintained at three‐month follow‐up.Positive benefits were observed for completion of MemFlex, and future comparison against an active intervention appears warranted.Further evaluation of MemFlex in this context may offer a low‐cost, and low‐resource intervention to improve access to psychological intervention for young migrants in low‐middle income countries. [ABSTRACT FROM AUTHOR]

The use of routinely collected electronic healthcare records (EHR) for outcome assessment in clinical trials has been described as a 'disruptive' new technique more than a decade ago. Despite this potential, significant methodological issues and regulatory barriers have hampered the progress in this area. This article discusses the key considerations that trialists should take into account when incorporating EHR into their trials. These include considerations of the clinical relevance of the outcome, data timeliness and quality, ethical and regulatory issues, and some practical considerations for clinical trials units. In addition, this article describes the benefits of using EHR which include cost, reduced trial burden for participants and staff, follow up efficiencies, and improved health economic evaluation procedures. We also describe the major regulatory and start up costs of using EHR in clinical trials. This article focuses on the UK specific EHR landscape in clinical trials and would help researchers and trials units considering the use of this method of outcome data collection in their next trial. If the issues described are mitigated, this method will be a formidable tool for conducting pragmatic clinical trials. [ABSTRACT FROM AUTHOR]

Background: Surgical trials are recognised as inherently challenging. Pilot and feasibility studies (PAFS) are increasingly acknowledged as a key method to optimise the design and conduct of randomised trials but remain limited in surgery. We used a mixed methods approach to develop recommendations for how surgical PAFS could be optimised. Methods: The findings from a quantitative analysis of funded surgical PAFS over a 10-year period and in-depth qualitative interviews with surgeons, methodologists and funders were triangulated and synthesised with available methodological guidance on PAFS. Results: The synthesis informed the development of an explanatory model describing root causes and compounding challenges that contribute to how and why surgical PAFS is not currently optimised. The four root causes identified include issues relating to (i) understanding the full scope of PAFS; (ii) design and conduct of PAFS; (iii) reporting of PAFS; and (iv) lack of appreciation of the value of PAFS by all stakeholder groups. Compounding challenges relate to both cultural issues and access to and interpretation of available methodological PAFS guidance. The study findings and explanatory model were used to inform the development of a practical guidance tool for surgeons and study teams to improve research practice. Conclusions: Optimisation of PAFS in surgery requires a cultural shift in research practice amongst funders, academic institutions, regulatory bodies and journal editors, as well as amongst surgeons. Our 'Top Tips' guidance tool offers an accessible framework for surgeons designing PAFS. Adoption and utilisation of these recommendations will optimise surgical PAFS, facilitating successful and efficient future surgical trials. [ABSTRACT FROM AUTHOR]

The purpose of this study was to assess the prevalence of multicenter studies in the orthopedic literature compared to general medicine and other surgical subspecialty studies as an update to a previous study. The number of multicenter research studies across three orthopedic surgery journals was higher in 2021 compared to 2009 (7.2% [95% CI: 5.1%−9.4%, χ2 [df = 1 = 43.8]], p < 0.0001), as was the number of authors and institutions listed on clinical research studies. While these trends in multicenter research publishing are encouraging, orthopedic surgery still lags behind the general medicine and other surgical subspecialty literature bases. Of the 934 orthopedic surgery studies published, 92 (9.9%) were multicenter studies compared to 64.4% of the general medicine and 26.9% of the other surgical subspecialty studies (χ2 [df = 2] = 472.6, p < 0.001). Multicenter trials conducted in orthopedics have fundamentally changed musculoskeletal care, affecting the lives of millions of patients. Participation in multicenter research should be encouraged and prioritized through continued advocacy, funding, support, and direction from orthopedic governing bodies, journals, and subspecialty groups. [ABSTRACT FROM AUTHOR]

Roman Republican elections especially during the Late Republic were a ubiquitous phenomenon. The small number of higher magistracies in comparison to the growing number of eligible candidates often led to a fierce competition within the political elite. To secure a win, competitors running for office made use of a whole spectrum of methods which often overstepped the legal and moral boundaries and eventually resulted in legal measures. The lex Licinia de sodaliciis enacted in 55 BCE is one of these measures. This article studies the lex by raising questions about its historic background, its target – electoral misconduct by organising sodalicia that is political associations within the voting districts – the trials conducted under the law, the effect associations had on Roman politics, and the Senate's effort to regulate them thorough legislation. [ABSTRACT FROM AUTHOR]

Background Since the onset of COVID-19, oncology practices across the US have integrated telemedicine (TM) and remote patient monitoring (RPM) into routine care and clinical trials. The extent of provider experience and comfort with TM/RPM in treatment trials, however, is unknown. We surveyed oncology researchers to assess experience and comfort with TM/RPM. Methods Between April 10 and June 1, 2022, we distributed email surveys to US-based members of the American Society of Clinical Oncology (ASCO) whose member records indicated interest or specialization in clinical research. We collected respondent demographic data, clinical trial experience, workplace characteristics, and comfort and experience with TM/RPM use across trial components in phase I and phase II/III trials. TM/RPM was defined as clinical trial-related healthcare and monitoring for patients geographically separated from trial site. Results There were 141 surveys analyzed (5.1% response rate). Ninety percent of respondents had been Principal Investigators, 98% practiced in a norural site. Most respondents had enrolled patients in phase I (82%) and phase II/III trials (99%). Across all phases and trial components, there was a higher frequency of researcher comfort compared to experience. Regarding remote care in treatment trials, 75% reported using TM, RPM, or both. Among these individuals, 62% had never provided remote care to trial patients before the pandemic. Conclusion COVID-19 spurred the rise of TM/RPM in cancer treatment trials, and some TM/RPM use continues in this context. Among oncology researchers, higher levels of comfort compared with real-world experience with TM/RPM reveal opportunities for expanding TM/RPM policies and guidelines in oncology research. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is one of the deadliest malignant tumors, which is a serious threat to human health and life, and it is expected that pancreatic cancer may be the second leading cause of cancer death in developed countries by 2030. Claudin18.2 is a tight junction protein expressed in normal gastric mucosal tissues, which is involved in the formation of tight junctions between cells and affects the permeability of paracellular cells. Claudin18.2 is highly expressed in pancreatic cancer and is associated with the initiation, progression, metastasis and prognosis of cancer, so it is considered a potential therapeutic target. Up to now, a number of clinical trials for Claudin18.2 are underway, including solid tumors such as pancreatic cancers and gastric cancers, and the results of these trials have not yet been officially announced. This manuscript briefly describes the Claudia protein, the dual roles of Cluadin18 in cancers, and summarizes the ongoing clinical trials targeting Claudin18.2 with a view to integrating the research progress of Claudin18.2 targeted therapy. In addition, this manuscript introduces the clinical research progress of Claudin18.2 positive pancreatic cancer, including monoclonal antibodies, bispecific antibodies, antibody-drug conjugates, CAR-T cell therapy, and hope to provide feasible ideas for the clinical treatment of Claudin18.2 positive pancreatic cancer. [ABSTRACT FROM AUTHOR]

The article discusses the benefits of two medications, dapagliflozin and empagliflozin, for heart failure. It emphasizes that the quality and quantity of life, as well as freedom from long-term disability, are important to patients. The article explains that while hospitalizations can be used as a measure of symptoms and well-being, there are other factors that can influence quality of life. The trials for these medications showed reductions in morbidity and possibly mortality, but the benefits were relatively small. The article suggests that the real therapeutic benefit of these medications may lie in their effects on symptoms and well-being. However, the trials did not show substantial improvement in symptoms for patients with heart failure. The article concludes that these medications should be offered widely to patients with heart failure who want to live longer, but may not be necessary for patients with few symptoms. [Extracted from the article]

Radiotherapy treatment planning hinges on a critical factor: the prescribed dose. Surprisingly, no consistent, standardised global approach to interpreting this prescription exists. This study aimed to examine and illustrate the variations in prescribed doses for the same treatment across North European and North American centres. The study analysed consecutively treated oropharynx cancer patients from six globally recognised radiotherapy departments. The criteria for inclusion encompassed curative IMRT or VMAT radiotherapy administered in 2017 or later. These centres were divided into three North American and three North European centres. Dose-volume histogram (DVH) data were extracted from the local treatment planning system for the Gross Tumour Volume (GTV), the high-dose Clinical Target Volume (CTV), and Planning Target Volume (PTV) for each patient. The DVH was sampled in 1 cGy dose bins across the 0 to 100 Gy range. All DVHs were scaled to a standard prescription of 70 Gy delivered in 35 fractions to facilitate straightforward comparisons across centres. No biological corrections were applied. For the three target volumes (GTV, CTV, PTV), we extracted and compared metrics such as D95% (Dose to 95% of the volume), D98%, D99%, V95% (Volume receiving 95% of the prescription dose), V105%, and V107%. We visually compared these metrics and conducted statistical testing using the Mann-Whitney U-test. Our study encompassed 1,375 patients treated across six centres, revealing a spectrum of 38 different dose prescriptions, ranging from 55 Gy in 20 to 70 Gy in 35 fractions. When normalised to 70 Gy, the median mean CTV dose exhibited a 4% difference, ranging from 70.12 Gy to 72.93 Gy across centres. Notably, the three European centres showed a high consistency, deviating by only 0.4%, while the three North American centres showed a slight variation within 2%. Figure 1 presents the mean CTV dose and the D98% boxplots. The interquartile range (IQR) for the mean CTV dose from 0.17 Gy to 1.22 Gy, with European centres showing the smallest IQR. [Display omitted] Examining the near-minimum CTV doses (D98% of CTV), we observed a range from 68.65 Gy to 70.96 Gy, with an IQR from 0.30 Gy to 1.15 Gy. A scatter plot of CTV mean dose against CTV D98% revealed distinct clusters for each of the six centres (Figure 2). Notably, the European centres cluster more densely compared to the North American centres. [Display omitted] The variation in prescribed doses for the same treatment regimen poses a significant challenge. Clinical interpretation of 70 Gy varies widely between centres and is influenced by each centre's individual experience, which, in turn, impacts the interpretation of published results. European centres primarily adhere to the ICRU dose prescription, targeting the median CTV dose. Conversely, North American centres tend to prescribe based on the minimum dose to the CTV or, in some cases, the PTV, as outlined in various RTOG protocols. Our study underscores that prescribing a dose of 70 Gy in 35 fractions for standard oropharynx cancer patients results in substantial variations in mean and near-minimum CTV doses. These dose prescription discrepancies significantly impact the interpretation of clinical trial outcomes comparison. Furthermore, this significant dosimetric variability has important implications for dose de-escalation strategies for HPV+ oropharynx cancer treatment. [ABSTRACT FROM AUTHOR]

Background and purpose: Early this century, the high risk strategy of primary stroke and cardiovascular disease (CVD) prevention for individuals shifted away from identifying (and treating, as appropriate) all at‐risk individuals towards identifying and treating individuals who exceed arbitrary thresholds of absolute CVD risk. The public health impact of this strategy is uncertain. Methods: In our systematic scoping review, the electronic databases (Scopus, MEDLINE, Embase, Google Scholar, Cochrane Library) were searched to identify and appraise publications related to primary CVD/stroke prevention strategies and their effectiveness published in any language from January 1990 to August 2023. Results: No published randomized controlled trial was found on the effectiveness of the high CVD risk strategy for primary stroke/CVD prevention. Targeting high CVD risk individuals excludes a large proportion of the population from effective blood‐pressure‐lowering and lipid‐lowering treatment and effective CVD prevention. There is also evidence that blood pressure lowering and lipid lowering are beneficial irrespective of blood pressure and cholesterol levels and irrespective of absolute CVD risk and that risk‐stratified pharmacological management of blood pressure and lipids to only high CVD risk individuals leads to significant underuse of blood‐pressure‐lowering and lipid‐lowering medications in individuals otherwise eligible for such treatment. Conclusions: Primary stroke and CVD prevention needs to be done in all individuals with increased risk of CVD/stroke. Pharmacological management of blood pressure and blood cholesterol should not be solely based on the high CVD risk treatment thresholds. International guidelines and global strategies for primary CVD/stroke prevention need to be revised. [ABSTRACT FROM AUTHOR]